Poricoic acid A activates AMPK to attenuate fibroblast activation and abnormal extracellular matrix remodelling in renal fibrosis.
AMP-Activated Protein Kinases
/ chemistry
Animals
Case-Control Studies
Cell Line
Dose-Response Relationship, Drug
Extracellular Matrix
/ drug effects
Fibroblasts
/ drug effects
Fibrosis
Humans
Kidney
/ drug effects
Kidney Diseases
/ drug therapy
Male
Mice, Inbred BALB C
Molecular Docking Simulation
Rats, Sprague-Dawley
Smad3 Protein
/ genetics
Transforming Growth Factor beta1
/ genetics
Triterpenes
/ chemistry
Ureteral Obstruction
/ drug therapy
AMPK
Chronic kidney disease
Extracellular matrix
Fibroblast
Fibrosis
poricoic acid A
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
07
10
2019
revised:
06
03
2020
accepted:
21
04
2020
pubmed:
28
5
2020
medline:
3
7
2020
entrez:
28
5
2020
Statut:
ppublish
Résumé
In chronic kidney disease, although fibrosis prevention is beneficial, few interventions are available that specifically target fibrogenesis. Poricoic acid A (PAA) isolated from Poria cocos exhibits anti-fibrotic effects in the kidney, however the underlying mechanisms remain obscure. We isolated PAA and investigated its effects and the underlying mechanisms in renal fibrosis. Unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (Nx) animal models and TGF-β1-induced renal fibroblasts (NRK-49F) were used to investigate the anti-fibrotic activity of PAA and its underlying mechanisms. Western blots, qRT-PCR, immunofluorescence staining, co-immunoprecipitation and molecular docking methods were used. Knock-down and knock-in of adenosine monophosphate-activated protein kinase (AMPK) in the UUO model and cultured NRK-49F cells were employed to verify the mechanisms of action of PAA. PAA improved renal function and alleviated fibrosis by stimulating AMPK and inhibiting Smad3 specifically in Nx and UUO models. Reduced AMPK activity was associated with Smad3 induction, fibroblast activation, and the accumulation and aberrant remodelling of extracellular matrix (ECM) in human renal puncture samples and cultured NRK-49F cells. PAA stimulated AMPK activity and decreased fibrosis in a dose-dependent manner, thus showing that AMPK was essential for PAA to exert its anti-fibrotic effects. AMPK deficiency reduced the anti-fibrotic effects of PAA, while AMPK overexpression enhanced its effect. PAA activated AMPK and further inhibited Smad3 specifically to suppress fibrosis by preventing aberrant ECM accumulation and remodelling and facilitating the deactivation of fibroblasts.
Sections du résumé
BACKGROUND
BACKGROUND
In chronic kidney disease, although fibrosis prevention is beneficial, few interventions are available that specifically target fibrogenesis. Poricoic acid A (PAA) isolated from Poria cocos exhibits anti-fibrotic effects in the kidney, however the underlying mechanisms remain obscure.
PURPOSE
OBJECTIVE
We isolated PAA and investigated its effects and the underlying mechanisms in renal fibrosis.
STUDY DESIGN
METHODS
Unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (Nx) animal models and TGF-β1-induced renal fibroblasts (NRK-49F) were used to investigate the anti-fibrotic activity of PAA and its underlying mechanisms.
METHODS
METHODS
Western blots, qRT-PCR, immunofluorescence staining, co-immunoprecipitation and molecular docking methods were used. Knock-down and knock-in of adenosine monophosphate-activated protein kinase (AMPK) in the UUO model and cultured NRK-49F cells were employed to verify the mechanisms of action of PAA.
RESULTS
RESULTS
PAA improved renal function and alleviated fibrosis by stimulating AMPK and inhibiting Smad3 specifically in Nx and UUO models. Reduced AMPK activity was associated with Smad3 induction, fibroblast activation, and the accumulation and aberrant remodelling of extracellular matrix (ECM) in human renal puncture samples and cultured NRK-49F cells. PAA stimulated AMPK activity and decreased fibrosis in a dose-dependent manner, thus showing that AMPK was essential for PAA to exert its anti-fibrotic effects. AMPK deficiency reduced the anti-fibrotic effects of PAA, while AMPK overexpression enhanced its effect.
CONCLUSION
CONCLUSIONS
PAA activated AMPK and further inhibited Smad3 specifically to suppress fibrosis by preventing aberrant ECM accumulation and remodelling and facilitating the deactivation of fibroblasts.
Identifiants
pubmed: 32460034
pii: S0944-7113(20)30063-5
doi: 10.1016/j.phymed.2020.153232
pii:
doi:
Substances chimiques
Smad3 Protein
0
Smad3 protein, rat
0
Transforming Growth Factor beta1
0
Triterpenes
0
poricoic acid A
0
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
153232Informations de copyright
Copyright © 2020 Elsevier GmbH. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest All the authors declared no competing interests.